Mitra Siddhartha, Tsvetkov Andrey S, Finkbeiner Steven
Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
J Biol Chem. 2009 Feb 13;284(7):4398-403. doi: 10.1074/jbc.M806269200. Epub 2008 Dec 10.
The accumulation of mutant protein in intracellular aggregates is a common feature of neurodegenerative disease. In Huntington disease, mutant huntingtin leads to inclusion body (IB) formation and neuronal toxicity. Impairment of the ubiquitin-proteasome system (UPS) has been implicated in IB formation and Huntington disease pathogenesis. However, IBs form asynchronously in only a subset of cells with mutant huntingtin, and the relationship between IB formation and UPS function has been difficult to elucidate. Here, we applied single-cell longitudinal acquisition and analysis to monitor mutant huntingtin IB formation, UPS function, and neuronal toxicity. We found that proteasome inhibition is toxic to striatal neurons in a dose-dependent fashion. Before IB formation, the UPS is more impaired in neurons that go on to form IBs than in those that do not. After forming IBs, impairment is lower in neurons with IBs than in those without. These findings suggest IBs are a protective cellular response to mutant protein mediated in part by improving intracellular protein degradation.
突变蛋白在细胞内聚集体中的积累是神经退行性疾病的一个常见特征。在亨廷顿舞蹈症中，突变的亨廷顿蛋白会导致包涵体（IB）形成和神经元毒性。泛素 - 蛋白酶体系统（UPS）功能受损与包涵体形成及亨廷顿舞蹈症发病机制有关。然而，包涵体仅在一部分含有突变亨廷顿蛋白的细胞中异步形成，且包涵体形成与UPS功能之间的关系一直难以阐明。在此，我们应用单细胞纵向采集和分析来监测突变亨廷顿蛋白包涵体的形成、UPS功能及神经元毒性。我们发现蛋白酶体抑制对纹状体神经元具有剂量依赖性毒性。在包涵体形成之前，后续会形成包涵体的神经元中UPS受损程度比不形成包涵体的神经元更高。形成包涵体后，有包涵体的神经元中损伤程度低于没有包涵体的神经元。这些发现表明，包涵体是对突变蛋白的一种保护性细胞反应，部分是通过改善细胞内蛋白质降解介导的。
